The Tumour Necrosis Factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in a wide variety of tumour cells in vivo without causing toxicity to normal cells (Ashkenazi et al., 1999; Walczak et al., 1999). Consequently, these findings have triggered the design of TRAIL-receptor (TRAIL-R) agonistic cancer therapies (WO 2002094880 A1, U.S. Pat. No. 7,915,245 B2). Yet, in recent years it has become apparent that human primary tumour cells are often resistant to TRAIL-mediated apoptosis (Todaro et al., 2008) and that TRAIL can also induce non-apoptotic signalling in cancer cells (Azijli et al., 2013; Newsom-Davis et al., 2009). Moreover, in many cancers the death-domain-containing TRAIL-Rs, i.e. TRAIL-R1 (Pan et al., 1997) (also known as DR4) and TRAIL-R2 (Walczak et al., 1997) (also known as KILLER, DRS, TRICK2A/TRICK2B, Apo2), the two apoptosis-inducing receptors for TRAIL, are expressed at higher levels than in normal tissue (Daniels et al., 2005; Ozawa et al., 2001; Spierings et al., 2003). Considering that these two receptors serve as therapeutic targets for agonists whose purpose it is to induce apoptosis, it seemed an advantageous coincidence that these receptors were expressed at higher levels in many cancers than in normal tissue. However, this observation also raised the question whether there could be a yet unknown and unexplored benefit for cancers to highly express these TRAIL-Rs.
In an earlier study, it was shown in a DMBA/TPA-induced mouse model of skin cancer that is typically driven by oncogenic mutations of the Harvey rat sarcoma viral oncogene homologue (HRAS), that murine TRAIL-R (mTRAIL-R) acts as a specific suppressor of lymph node metastases. The proposed mechanism for this effect was induction of cell death via mTRAIL-R following detachment of the cancer cells from the primary tumour (Grosse-Wilde et al., 2008). Conversely, in another study to which one of us (H.W.) also contributed it was shown that human and murine colorectal cancer cell lines in which the Kirsten rat sarcoma viral oncogene homologue (KRAS) is oncogenically mutated were not only resistant to TRAIL- and CD95L-mediated apoptosis induction but that stimulation by these ligands increased motility and membrane ruffling in these cells (Hoogwater et al., 2010). The conclusion of that study was that patients with KRAS-mutated cancers should not be treated with TRAIL-R agonists (Hoogwater et al., 2010).
Oncogenic mutation of KRAS is very frequent in pancreatic cancer (Hidalgo, 2010; Jaffee et al., 2002), frequent in colon (Grady and Markowitz, 2002) and lung cancer (Mitsuuchi and Testa, 2002) and also occurs, albeit at much lower frequencies, in other cancer types such as biliary tract malignancies, endometrial cancer (Ito et al., 1996), cervical cancer (Wegman et al., 2011), bladder cancer (Przybojewska et al., 2000), liver cancer and cholangiocarcinoma (Boix-Ferrero et al., 2000), myeloid leukemia (Ahmad et al., 2009) and breast cancer (Karnoub and Weinberg, 2008). These are some of the most aggressive human cancers and despite many efforts to design efficient therapies for them, survival rates of patients with cancers that bear oncogenic KRAS mutations are still very low. In some cases oncogenic mutation of KRAS is even an exclusion criterion for treatment by certain drugs because they have been found to be ineffective in these patients (Amado et al., 2008; Deschoolmeester et al., 2010; Karapetis et al., 2008; van Krieken et al., 2008). The aggressive behaviour of KRAS-mutated cancers can be attributed to their inherent chemo-resistance, strong invasiveness and capacity to metastasize (Downward, 2003), traits which render these cancers very difficult to treat (Chaffer and Weinberg, 2011). However, the effector mechanisms mediating invasiveness and metastasis of KRAS-mutated cancers are only incompletely understood and, importantly, have so far escaped therapeutic intervention.
It will be appreciated from the forgoing that the provision of methods and materials directed to the treatment of KRAS-mutated cancers, or cancers in which similar pathological pathways or mechanisms are present, would provide a useful contribution to the art